title: A population genetic approach to mapping neurological disorder genes using deep resequencing.
abstract: Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n  =  285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders.
authors.affiliation: Department of Pediatrics, University of Montreal, Montreal, Canada.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Myers
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Jon
authors.initials: J
authors.lastname: Keebler
authors.forename: Adam R
authors.initials: AR
authors.lastname: Boyko
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: Amelie M
authors.initials: AM
authors.lastname: Piton
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Edouard
authors.initials: E
authors.lastname: Henrion
authors.forename: Martine
authors.initials: M
authors.lastname: Zilversmit
authors.forename: Julie
authors.initials: J
authors.lastname: Hussin
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Quinlan
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Griffing
authors.forename: Eric A
authors.initials: EA
authors.lastname: Stone
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D005828:Genetics, Population; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA